Single-dose Effectiveness of Mpox Vaccine in Quebec, Canada: Test-negative Design With and Without Adjustment for Self-reported Exposure Risk.

INTRODUCTION: During the 2022 mpox outbreak, the province of Quebec, Canada, prioritized first doses for pre-exposure vaccination of people at high mpox risk, delaying second doses due to limited supply. We estimated single-dose mpox vaccine effectiveness (VE) adjusting for virus exposure risk based only on surrogate indicators available within administrative databases (eg, clinical record of sexually transmitted infections) or supplemented by self-reported risk factor information (eg, sexual contacts). METHODS: We conducted a test-negative case-control study between 19 June and 24 September 2022. Information from administrative databases was supplemented by questionnaire collection of self-reported risk factors specific to the 3-week period before testing. Two study populations were assessed: all within the administrative databases (All-Admin) and the subset completing the questionnaire (Sub-Quest). Logistic regression models adjusted for age, calendar-time and exposure-risk, the latter based on administrative indicators only (All-Admin and Sub-Quest) or with questionnaire supplementation (Sub-Quest). RESULTS: There were 532 All-Admin participants, of which 199 (37%) belonged to Sub-Quest. With exposure-risk adjustment based only on administrative indicators, single-dose VE estimates were similar among All-Admin and Sub-Quest populations at 35% (95% confidence interval [CI]:-2 to 59) and 30% (95% CI:-38 to 64), respectively. With adjustment supplemented by questionnaire information, the Sub-Quest VE estimate increased to 65% (95% CI:1-87), with overlapping confidence intervals. CONCLUSIONS: Using only administrative data, we estimate one vaccine dose reduced the mpox risk by about one-third; whereas, additionally adjusting for self-reported risk factor information revealed greater vaccine benefit, with one dose instead estimated to reduce the mpox risk by about two-thirds. Inadequate exposure-risk adjustment may substantially under-estimate mpox VE.

Human Immunodeficiency Virus Treatment Attitudes and Bacterial Sexually Transmitted Infections Among Gay and Bisexual Men.

BACKGROUNDS: Positive attitudes toward human immunodeficiency virus (HIV) treatment, such as reduced concern about HIV transmissibility, are associated with sexual behaviors that may increase the risk of bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (GBM). We examined associations between HIV treatment attitudes and bacterial STI diagnoses among GBM in Canada's three largest cities. METHODS: We fit a structural equation model between HIV treatment attitudes and bacterial STI diagnoses via sexual behaviors in the Engage study's baseline data. We estimated direct and indirect paths between scores on HIV treatment attitudes and STIs via number of male anal sex partners, condomless anal sex, and oral sex. We conducted sub-analyses with participants stratified by HIV serostatus. RESULTS: Among 2449 GBM recruited in 2017 to 2019, there was a direct association between HIV treatment attitudes and current STI diagnoses (ß = 0.13; 95% CI, 0.07-0.19; P < 0.001). The mediated model revealed a positive total indirect effect through 2 pathways: (1) engaging in condomless anal sex and (2) number of male anal sex partners and condomless anal sex. These 2 indirect pathways remained in the stratified mediation models for both HIV negative GBM and for GBM living with HIV. CONCLUSIONS: The association between HIV treatment attitudes and diagnosed STIs is mediated through a higher number of male anal sex partners and condomless anal sex. The results highlight the importance of providers educating patients when providing effective STI counseling, testing, and prevention for GBM about how accurate HIV treatment attitudes may inadvertently be associated with the bacterial STI epidemic.

End of selection criteria based on sexual orientation: An international symposium on alternatives to donation deferral.

BACKGROUND AND OBJECTIVES: Until recently, gay, bisexual and other men who have sex with men (MSM) were deferred from donating blood for 3-12 months since the last male-to-male sexual contact. This MSM deferral has been discontinued by several high-income countries (HIC) that now perform gender-neutral donor selection. MATERIALS AND METHODS: An international symposium (held on 20-04-2023) gathered experts from seven HICs to (1) discuss how this paradigm shift might affect the mitigation strategies for transfusion-transmitted infections and (2) address the challenges related to gender-neutral donor selection. RESULTS: Most countries employed a similar approach for implementing a gender-neutral donor selection policy: key stakeholders were consulted; the transition was bridged by time-limited deferrals; donor compliance was monitored; and questions or remarks on anal sex and the number and/or type of sexual partners were often added. Many countries have now adopted a gender-neutral approach in which questions on pre- and post-exposure prophylaxis for human immunodeficiency virus (HIV) have been added (or retained, when already in place). Other countries used mitigation strategies, such as plasma quarantine or pathogen reduction technologies for plasma and/or platelets. CONCLUSION: The experience with gender-neutral donor selection has been largely positive among the countries covered herein and seems to be acceptable to stakeholders, donors and staff. The post-implementation surveillance data collected so far appear reassuring with regards to safety, although longer observation periods are necessary. The putative risks associated with HIV antiretrovirals should be further investigated.

HIV Treatment Optimism Moderates the Relationship between Sexual Risk Behavior and HIV Risk Perception among Urban HIV-negative Gay, Bisexual, and Other Men who have Sex With Men.

Using baseline data of the Engage Cohort Study, a Canadian study of sexually active gay, bisexual and other men who have sex with men (GBM), we evaluated the association between sexual behavior and risk perception among HIV-negative participants and whether HIV treatment optimism moderated this relationship. Participants were recruited by respondent-driven-sampling (RDS). We defined high-risk sexual behavior in the past six months as any condomless anal sex with a casual partner (i.e. not the participant's main partner) with either unknown HIV-status where neither used pre-exposure prophylaxis or with a partner living with HIV having detectable/unknown viral load. We assessed HIV treatment optimism-skepticism using a 12-item scale. RDS-II-weighted adjusted logistic regression models examined associations with risk perception measured by the question "How would you assess your current risk of getting HIV?" (response options were on a 6-point Likert-scale ranging from "very unlikely" to "very likely", dichotomized into "No Perceived Risk" (very unlikely/unlikely) and "Perceived Risk" (somewhat likely/likely/very likely/I think I already have HIV). Of 1961 participants, engagement in high-risk sexual behavior was reported by 155 (17.0%), 62 (12.4%), 128 (17.2%) of participants in Montréal, Toronto, and Vancouver, respectively. High-risk sexual behavior increased the odds of perceived HIV risk (pooled adjusted odds ratio = 2.9, 95%CI = 2.2-3.8). HIV treatment optimism-skepticism scores moderated the relationship: for GBM engaging in high-risk sexual behavior, higher HIV treatment optimism-skepticism scores increased perceived HIV risk. Promoting awareness around advances related to HIV prevention and treatment is important for appropriate risk assessment and for increased engagement in prevention interventions.

RESUMEN: Evaluamos la asociación entre el comportamiento sexual y la percepción de riesgo entre los participantes VIH negativos y si el optimismo sobre el tratamiento del VIH moderó esta asociación. Definimos comportamiento sexual de alto riesgo en los últimos seis meses como cualquier sexo anal sin condón con una pareja casual con un estado de VIH desconocido donde ninguno utilizó profilaxis previa a la exposición o con una pareja que vive con el VIH y que tiene una carga viral detectable/desconocida. Se evaluó el optimismo sobre el tratamiento del VIH mediante una escala de 12 ítems. Los modelos de regresión logística ajustados examinaron las asociaciones con la percepción del riesgo ("Riesgo no percibido" vs. "Riesgo percibido"). De 1961 participantes, 155 (17,0%), 62 (12,4%), 128 (17,2%) de los participantes en Montreal, Toronto y Vancouver, informaron comportamiento sexual de alto riesgo. El comportamiento sexual de alto riesgo se mostró asociado con riesgo percibido. El optimismo sobre el tratamiento modero la asociación. Promover la conciencia sobre los avances relacionados con la prevención y el tratamiento del VIH es importante para una evaluación adecuada de los riesgos y una mayor participación en las intervenciones de prevención.

Attitudes of Gay, Bisexual, and Other Men Who Have Sex with Men (GBM) toward Their Use of Amphetamine-Type Stimulants and Relation to Reducing Use in Three Canadian Cities.

BACKGROUND: We explored attitudes of gay, bisexual, and other men who have sex with men (GBM) toward their amphetamine-use and associations with reduced use over time. METHODS: We recruited sexually-active GBM aged 16+ years in Montreal, Toronto, and Vancouver, Canada, from 02-2017 to 08-2019, with follow-up visits every 6-12 months until November 2020. Among participants who reported past-six-month (P6M) amphetamine-use at enrollment, we used logistic regression to identify demographic, psychological, social, mental health, other substance-use, and behavioral factors associated with reporting needing help reducing their substance-use. We used mixed-effects logistic regression to model reduced P6M amphetamine-use with perceived problematic-use as our primary explanatory variable. RESULTS: We enrolled 2,449 GBM across sites. 15.5-24.7% reported P6M amphetamine-use at enrollment and 82.6 - 85.7% reported needing no help or only a little help in reducing their substance use. Reporting needing a lot/of help or completely needing help in reducing substance-use was associated with group sex participation (AOR = 2.35, 95%CI:1.25-4.44), greater anxiety symptomatology (AOR = 2.11, 95%CI:1.16-3.83), greater financial strain (AOR = 1.35, 95%CI:1.21-1.50), and greater Escape Motive scores (AOR = 1.07, 95%CI:1.03-1.10). Reductions in P6M amphetamine-use were less likely among GBM who perceived their amphetamine-use as problematic (AOR = 0.17 95% CI 0.10 - 0.29). CONCLUSIONS: Most amphetamine-using GBM did not feel they needed help reducing their substance use, and many reported reduced amphetamine-use at subsequent visits. Those who perceived their use as problematic were less likely to reduce their use. Further interventions to assist GBM in reducing their use are needed to assist those who perceive their use as problematic.

Minority Stress, Psychological Distress, Sexual Compulsivity, and Avoidance-Based Motivations Associated with Methamphetamine Use Among Sexual Minority Men Living with HIV: Examining Direct and Indirect Associations Using Cross-Sectional Structural Equation Modeling.

OBJECTIVE: Sexual minority men (SMM) living with HIV report significantly greater methamphetamine use compared with heterosexual and HIV-negative peers. Greater use may be related to stressors (e.g., HIV-related stigma) faced by SMM living with HIV and subsequent psychological and behavioral sequelae. We tested an integrated theoretical model comprised of pathways between stigma, discrimination, childhood sexual abuse, psychological distress, sexual compulsivity, and cognitive escape in predicting methamphetamine use among SMM living with HIV. METHODS: Among 423 SMM living with HIV, we tested a structural equation model examining factors hypothesized to be directly and indirectly associated with methamphetamine use. Analyses were adjusted for demographic covariates and sampling bias. RESULTS: The model showed good fit (CFI = 0.96, RMSEA = 0.01). Heterosexist discrimination was associated with psychological distress (ß = 0.39, p < 0.001) and psychological distress was associated with sexual compulsivity (ß = 0.33, p < 0.001). Sexual compulsivity was associated with cognitive escape (ß = 0.31, p < 0.001), which was associated with methamphetamine use (ß = 0.51, p < 0.001). Psychological distress was associated with methamphetamine use via serial indirect effects of sexual compulsivity and cognitive escape (ß = 0.05, p < 0.05). CONCLUSIONS: Heterosexist discrimination contributed to psychological distress among SMM living with HIV. Psychological distress is linked to methamphetamine use via sexual compulsivity and cognitive avoidance. Interventions seeking to reduce the likelihood that SMM living with HIV use methamphetamine should include coping strategies specific to heterosexism and related psychological distress.

Vaccine Effectiveness Against 12-Month Incident and Persistent Anal Human Papillomavirus Infection Among Gay, Bisexual, and Other Men Who Have Sex With Men.

BACKGROUND: Real-world evidence of human papillomavirus (HPV) vaccine effectiveness (VE) against longitudinal outcomes is lacking among gay, bisexual, and other men who have sex with men (GBM). We compared 12-month incidence and persistence of anal HPV infection between vaccinated and unvaccinated GBM. METHODS: We recruited GBM aged 16-30 years in Montreal, Toronto, and Vancouver, Canada, from 2017 to 2019. Participants were followed over a median of 12 months (interquartile range, 12-13 months). Participants self-reported HPV vaccination and self-collected anal specimens for HPV DNA testing. We calculated prevalence ratios (PR) for 12-month cumulative incidence and persistence with ≥1 quadrivalent vaccine type (HPV 6/11/16/18) between vaccinated (≥1 dose at baseline) and unvaccinated participants using a propensity score-weighted, modified Poisson regression. RESULTS: Among 248 participants, 109 (44.0%) were vaccinated at baseline, of whom 62.6% received 3 doses. PRs for HPV 6/11/16/18 were 0.56 (95% confidence interval [CI], .24-1.31) for cumulative incidence and 0.53 (95% CI, .25-1.14) for persistence. PRs were 0.23 (95% CI, .05-1.03) and 0.08 (95% CI, .01-.59) for incidence and persistence, respectively, among participants who received their first dose at age ≤23 years and 0.15 (95% CI, .03-.68) and 0.12 (95% CI, .03-.54) among participants who were sexually active for ≤5 years before vaccination. CONCLUSIONS: Findings support national recommendations for HPV vaccination at younger ages or soon after sexual debut.

PCSK9 and the nervous system: a no-brainer?

In the past 20 years, PCSK9 has been shown to play a pivotal role in LDL cholesterol metabolism and cardiovascular health by inducing the lysosomal degradation of the LDL receptor. PCSK9 was discovered by the cloning of genes up-regulated after apoptosis induced by serum deprivation in primary cerebellar neurons, but despite its initial identification in the brain, the precise role of PCSK9 in the nervous system remains to be clearly established. The present article is a comprehensive review of studies published or in print before July 2023 that have investigated the expression pattern of PCSK9, its effects on lipid metabolism as well as its putative roles specifically in the central and peripheral nervous systems, with a special focus on cerebrovascular and neurodegenerative diseases.

Self-reported Human Papillomavirus Vaccination and Vaccine Effectiveness Among Men Who Have Sex with Men: A Quantitative Bias Analysis.

BACKGROUND: Self-report of human papillomavirus (HPV) vaccination has ~80-90% sensitivity and ~75-85% specificity. We measured the effect of nondifferential exposure misclassification associated with self-reported vaccination on vaccine effectiveness (VE) estimates. METHODS: Between 2017-2019, we recruited sexually active gay, bisexual, and other men who have sex with men aged 16-30 years in Canada. VE was derived as 1-prevalence ratio × 100% for prevalent anal HPV infection comparing vaccinated (≥1 dose) to unvaccinated men using a multivariable modified Poisson regression. We conducted a multidimensional and probabilistic quantitative bias analysis to correct VE estimates. RESULTS: Bias-corrected VE estimates were relatively stable across sensitivity values but differed from the uncorrected estimate at lower values of specificity. The median adjusted VE was 27% (2.5-97.5th simulation interval = -5-49%) in the uncorrected analysis, increasing to 39% (2.5-97.5th simulation interval = 2-65%) in the bias-corrected analysis. CONCLUSION: A large proportion of participants erroneously reporting HPV vaccination would be required to meaningfully change VE estimates.

Pre-exposure prophylaxis and bacterial sexually transmitted infections (STIs) among gay and bisexual men.

OBJECTIVES: While pre-exposure prophylaxis (PrEP) prevents HIV acquisition among gay, bisexual and other men who have sex with men (GBM), PrEP-using GBM may be more likely to engage in sexual behaviours associated with bacterial STIs. We examined associations between PrEP use, condomless anal sex (CAS), number of anal sex partners, oral sex and bacterial STI diagnoses among GBM living in Canada's three largest cities. METHODS: Among HIV-negative/unknown-status GBM in the baseline of the Engage cohort study, we fit a structural equation model of the associations between any PrEP use, sexual behaviours and bacterial STI diagnosis. We estimated direct and indirect paths between PrEP use and STI via CAS, number of anal sex partners and oral sex. RESULTS: The sample included 2007 HIV-negative/unknown status GBM in Montreal, Toronto and Vancouver. There was a significant direct association between PrEP use and current STI diagnosis (ß=0.181; 95% CI: 0.112 to 0.247; p<0.001), CAS (ß=0.275; 95% CI: 0.189 to 0.361; p<0.001) and number of anal sex partners (ß=0.193; 95% CI: 0.161 to 0.225; p<0.001). In the mediated model, the direct association between PrEP use and STIs was non-significant. However, the indirect paths from PrEP to CAS to STIs (ß=0.064; 95% CI: 0.025 to 0.120; p=0.008), and from PrEP to greater number of anal sex partners to CAS to STIs were significant (ß=0.059; 95% CI: 0.024 to 0.108; p=0.007). CONCLUSIONS: Our study adds to the growing awareness that PrEP use among GBM may be associated with bacterial STIs because PrEP users have more anal sex partners and are more likely to engage in CAS. The results underscore the importance of providing effective STI counselling and regular testing to PrEP users, adapting PrEP care and related STI testing to individual needs, and the need for effective prevention strategies for bacterial STIs.

HDL as a Treatment Target: Should We Abandon This Idea?

PURPOSE OF REVIEW: High-density lipoproteins (HDL) have long been regarded as an antiatherogenic lipoprotein species by virtue of their role in reverse cholesterol transport (RCT), as well as their established anti-inflammatory and antioxidant properties. For decades, HDL have been an extremely appealing therapeutic target to combat atherosclerotic cardiovascular diseases (ASCVD). RECENT FINDINGS: Unfortunately, neither increasing HDL with drugs nor direct infusions of reconstituted HDL have convincedly proven to be positive strategies for cardiovascular health, raising the question of whether we should abandon the idea of considering HDL as a treatment target. The results of two large clinical trials, one testing the latest CETP inhibitor Obicetrapib and the other testing the infusion of patients post-acute coronary events with reconstituted HDL, are still awaited. If they prove negative, these trials will seal the fate of HDL as a direct therapeutic target. However, using HDL as a therapeutic agent still holds promise if we manage to optimize their beneficial properties for not only ASCVD but also outside the cardiovascular field.

Associated criteria used in investigating suspected septic transfusion reactions: A scoping review.

BACKGROUND AND OBJECTIVES: Septic transfusion reactions (STRs) occur as a result of bacterial contamination of blood or blood products, resulting in sepsis. This scoping review aimed to identify, explore and map the available literature on the STR criteria triggering the investigation of STR. MATERIALS AND METHODS: Four electronic databases (MEDLINE, Web of Science, Science Direct, Embase) were searched to retrieve scientific literature reporting such criteria, published from 1 January 2000 to 5 May 2022. Grey literature was also searched from open web sources. RESULTS: Of 1052 references identified, 43 (21 peer-reviewed and 22 grey literature) met the eligibility criteria for inclusion and data extraction after full article screening. Of them, most (27/43, 62.79%) were found to report a single set of criteria, and only two reported four or more sets of criteria. The analysis of 66 sets of criteria collected from the selected references revealed 57 different sets. A few sets of criteria used only one sign and symptom (s/s) (12.12%, n = 8), whereas 16 sets used 7-15 s/s (n = 16/66; 24.24%). Of the total 319 occurrences of s/s associated with the 66 sets of criteria, post-transfusion hyperthermia, body temperature increase and hypotension were the most common s/s categories. Of all the literature available, only one study tested the diagnostic accuracy of the STR criteria. CONCLUSION: This scoping review revealed a substantial variation in criteria used to identify suspected STR. Consequently, conducting further studies to enhance the diagnostic accuracy of these criteria, which trigger STR investigations, is imperative for advancing clinical practice.

Leu22_Leu23 Duplication at the Signal Peptide of PCSK9 Promotes Intracellular Degradation of LDLr and Autosomal Dominant Hypercholesterolemia.

BACKGROUND: PCSK9 (Proprotein convertase subtilisin/kexin type 9) regulates LDL-C (low-density lipoprotein cholesterol) metabolism by targeting LDLr (LDL receptor) for lysosomal degradation. PCSK9 gain-of-function variants cause autosomal dominant hypercholesterolemia by reducing LDLr levels, the D374Y variant being the most severe, while loss-of-function variants are associated with low LDL-C levels. Gain-of-function and loss-of-function activities have also been attributed to variants occurring in the PCSK9 signal peptide. Among them, L11 is a very rare PCSK9 variant that seems to increase LDL-C values in a moderate way causing mild hypercholesterolemia. METHODS: Using molecular biology and biophysics methodologies, activities of L8 and L11 variants, both located in the leucine repetition stretch of the signal peptide, have been extensively characterized in vitro. RESULTS: L8 variant is not associated with increased LDLr activity, whereas L11 activity is increased by ≈20% compared with wt PCSK9. The results suggest that the L11 variant reduces LDLr levels intracellularly by a process resulting from impaired cleavage of the signal peptide. This would lead to less efficient LDLr transport to the cell membrane and promote LDLr intracellular degradation. CONCLUSIONS: Deletion of a leucine in the signal peptide in L8 variant does not affect PCSK9 activity, whereas the leucine duplication in the L11 variant enhances LDLr intracellular degradation. These findings highlight the importance of deep in vitro characterization of PCSK9 genetic variants to determine pathogenicity and improve clinical diagnosis and therapy of inherited familial hypercholesterolemia disease.

Examining differential success in recruitment using respondent driven sampling (RDS) in a multi-site study of gay, bisexual and other men who have sex with men.

BACKGROUND: The Engage Study is a longitudinal biobehavioral cohort study of gay, bisexual and other men who have sex with men (GBM) in Toronto, Montreal, and Vancouver. Baseline data (2,449 participants) were collected from February 2017 - August 2019 using respondent-driven sampling (RDS). Recruitment in Montreal required fewer seeds, had a much shorter recruitment period, and recruited the largest sample. METHODS: To better understand why RDS recruitment was more successful in Montreal compared to other sites, we conducted an analysis to examine RDS recruitment characteristics for GBM in each of the three study sites, explore demographic characteristics and measures of homophily, that is, the tendency of individuals to recruit other study participants who are like themselves, and compared motivations for study participation. RESULTS: Montreal had the greatest proportion of participants over the age of 45 (29.1% in Montreal, 24.6% in Vancouver, and 21.0% in Toronto) and the highest homophily for this age group, but homophily was high across the three cities. Montreal also reported the lowest percentage of participants with an annual income greater or equal to $60,000 (7.9% in Montreal, 13.1% in Vancouver and 10.6% in Toronto), but homophily was similar across all three cities. The majority of participants indicated interest in sexual health and HIV as the main reason for participating (36.1% in Montreal, 34.7% in Vancouver, and 29.8% in Toronto). Financial interest as the main reason for participation was low (12.7% in Montreal, 10.6% in Vancouver, and 5.7% in Toronto). CONCLUSION: Taken together, although we found some differences in study demographic characteristics and homophily scores, we were unable to fully explain the different recruitment success based on the data available. Our study underlines the fact that success of RDS implementation may vary by unknown factors, and that researchers should be proactive and flexible to account for variability.

Examining Associations Between Resilience and PrEP Use Among HIV-negative GBM in Toronto, Montreal and Vancouver.

This study evaluated the association between resilience and PrEP use among a population-based sample of Canadian gay, bisexual, and other men who have sex with men (GBM). Sexually active GBM aged ≥ 16 years old were recruited via respondent-driven sampling (RDS) in Toronto, Montreal, and Vancouver from 02/2017 to 07/2019. We conducted a pooled cross-sectional analysis of HIV-negative/unknown GBM who met clinical eligibility for PrEP. We performed multivariable RDS-II-weighted logistic regression to assess the association between scores on the Connor-Davidson Resilience-2 Scale and PrEP. Mediation analyses with weighted logistic and linear regression were used to assess whether the relationship between minority stressors and PrEP use was mediated by resilience. Of 1167 PrEP-eligible GBM, 317 (27%) indicated they took PrEP in the past six months. Our multivariable model found higher resilience scores were associated with greater odds of PrEP use in the past six months (aOR = 1.13, 95%CI = 1.00, 1.28). We found that resilience reduced the effect of the association between heterosexist discrimination and PrEP use. Resilience also mediated the relationship between internalized homonegativity and PrEP use and mediated the effect of the association between LGBI acceptance concern and PrEP use. Overall, PrEP-eligible GBM with higher resilience scores had a greater odds of PrEP use in the past six months. We also found mixed results for the mediating role of resilience between minority stress and PrEP use. These findings underline the continued importance of strength-based factors in HIV prevention.

Examining the secondary impacts of the COVID-19 pandemic on syndemic production and PrEP use among gay, bisexual and other men who have sex with men (GBM) in Vancouver, Canada.

BACKGROUND: The secondary impacts of the COVID-19 pandemic may disproportionately affect gay, bisexual, and other men who have sex with men (GBM), particularly related to HIV prevention and treatment outcomes. We applied syndemic theory to examine PrEP disruptions during the during the height of the COVID-19 pandemic in Vancouver, Canada. METHODS: Sexually-active GBM, aged 16 + years, were enrolled through respondent-driven sampling (RDS) from February 2017 to August 2019. Participants completed a Computer-Assisted Self-Interview every six months and data were linked to the BC PrEP Program (program responsible for publicly funded PrEP in the province) to directly measure PrEP disruptions. The analysis period for this study was from March 2018-April 2021. We used univariable generalized linear mixed models to examine (1) six-month trends for syndemic conditions: the prevalence of moderate/severe depressive or anxiety symptoms, polysubstance use, harmful alcohol consumption, intimate partner violence, and (2) six-month trends for PrEP interruptions among HIV-negative/unknown GBM. We also applied 3-level mixed-effects logistic regression with RDS clustering to examine whether syndemic factors were associated with PrEP interruptions. RESULTS: Our study included 766 participants, with 593 participants who had at least one follow-up visit. The proportion of respondents with abnormal depressive symptoms increased over the study period (OR = 1.35; 95%CI = 1.17, 1.56), but we found decreased prevalence for polysubstance use (OR = 0.89; 95%CI = 0.82, 0.97) and binge drinking (OR = 0.74; 95%CI = 0.67, 0.81). We also found an increase in PrEP interruptions (OR = 2.33; 95%CI = 1.85, 2.94). GBM with moderate/severe depressive symptoms had higher odds (aOR = 4.80; 95%CI = 1.43, 16.16) of PrEP interruptions, while GBM with experiences of IPV had lower odds (aOR = 0.38; 95%CI = 0.15, 0.95) of PrEP interruptions. GBM who met clinical eligibility for PrEP had lower odds of experiencing PrEP interruptions (aOR = 0.25; 95%CI = 0.11, 0.60). CONCLUSION: There were increasing PrEP interruptions since March 2020. However, those most at risk for HIV were less likely to have interruptions. Additional mental health services and targeted follow-up for PrEP continuation may help to mitigate the impacts of the COVID-19 pandemic on GBM.

'I did not have sex outside of our bubble': changes in sexual practices and risk reduction strategies among sexual minority men in Canada during the COVID-19 pandemic.

In efforts to prevent the spread of COVID-19, jurisdictions across the globe, including Canada, enacted containment measures that affected intimacy and sexual relations. This article examines how public health measures during COVID-19 impacted the sexual practices of sexual minority men- gay, bisexual, queer and other men who have sex with men-and how they adopted and modified guidelines to prevent the transmission of COVID-19, HIV and other sexually transmitted infections (STIs). We conducted 93 semi-structured interviews with men (n = 93) in Montreal, Toronto and Vancouver, Canada, between November 2020 to February 2021 (n = 42) and June to October 2021 (n = 51). Across jurisdictions, participants reported changes to sexual practices in response to public health measures and shifting pandemic contexts. Many men indicated that they applied their HIV/STI risk mitigation experiences and adapted COVID-19 prevention strategies to continue engaging in casual sexual behaviours and ensure sexual safety. 'Social bubbles' were changed to 'sex bubbles'. Masks were turned into 'safer' sex tools. 'Outdoor gathering' and 'physical distancing' were transformed into 'outdoor sex' and 'voyeuristic masturbation'. These strategies are examined in connection to the notion of 'reflexive mediation' to illustrate how sexual minority men are simultaneously self-responsibilising and resistant, self-monitoring and creative.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo.

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to cardiovascular disease, PCSK9 has attracted intense interest as a therapeutic target. Despite this interest, an orally bioavailable small-molecule inhibitor of PCSK9 with extensive lipid-lowering activity is yet to enter the clinic. We report herein the discovery of NYX-PCSK9i, an orally bioavailable small-molecule inhibitor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE∗3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chemistry campaign demonstrating potent disruption of the PCSK9-LDLR interaction in vitro and functional protection of the LDLR of human lymphocytes from PCSK9-directed degradation ex vivo. APOE∗3-Leiden.CETP mice orally treated with NYX-PCSK9i demonstrated a dose-dependent decrease in plasma total cholesterol of up to 57%, while its combination with atorvastatin additively suppressed plasma total cholesterol levels. Importantly, the majority of cholesterol lowering by NYX-PCSK9i was in non-HDL fractions. A concomitant increase in total plasma PCSK9 levels and significant increase in hepatic LDLR protein expression strongly indicated on-target function by NYX-PCSK9i. Determinations of hepatic lipid and fecal cholesterol content demonstrated depletion of liver cholesteryl esters and promotion of fecal cholesterol elimination with NYX-PCSK9i treatment. All measured in vivo biomarkers of health indicate that NYX-PCSK9i has a good safety profile. NYX-PCSK9i is a potential new therapy for hypercholesterolemia with the capacity to further enhance the lipid-lowering activities of statins.

Plasma apolipoprotein concentrations and incident diabetes in subjects with prediabetes.

BACKGROUND: The identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up. METHODS: In the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110-125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman's coefficients. Kaplan-Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models. RESULTS: During a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA1c, and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p = 0.010), apoF (1.22 [1.01; 1.48]; p = 0.037), apoJ (1.24 [1.03; 1.49]; p = 0.024), and apoL1 (1.26 [1.05; 1.52]; p = 0.014) remained significantly associated with the onset of T2D. Kaplan-Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p = 0.002) compared to the middle and upper thirds. CONCLUSIONS: The plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations. Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509.